New theoretical techniques are being developed and characterized. These efforts are usually coupled with software development, and involve the systematic testing and evaluation of new ideas. This development is driven by current needs and interests. Specific projects include: - Enhancements in the development of Particle Mesh Ewald (PME) methods - Development of Ewald summation net-charge corrections(PME) - Calculation of free energies in periodic systems when the net-charge changes using PME - Use of a FFT filter function with PME for rapid evaluation of electrostatics interactions for finite systems - Development of methods for examining reaction mechanism in complex systems. - Development of the REPLICA/PATH method for determining reaction paths in complex systems - Development of combined Quantum Mechanical/Molecular Modeling (QM/MM) potentials (Gaussian delocalize MM charges, double link atom method) - Evaluation of alternate treatments of QM/MM interfaces - Calculation of pK of acids groups using Free Energy Perturbation and PME corrections. - Development of improved integration techniques for molecular dynamics - Development of a Non-reversible RESPA integrator for improved molecular dynamics simulations using a multiple timestep method - Development of flexible constraints MD techniques - Evaluation of Locally Enhanced Sampling (LES) for conformational searching - New constraint integrator; rigid bodies, massless lonepairs, and other contraint sites - Other method development - Development of RMS best-fit restraints; accurate forces, relative restraints - Rational drug design: shape descriptor facility for CHARMM - Development of accurate interaction energy calculations for macromolecules - Evaluation of small molecule/protein binding energy prediction methods - Development of a rapid search strategy for docking two macromolecules In recent years the Smooth Particle Mesh Ewald (PME) algorithm has become the method of choice in molecular dynamics simulations with periodic boundary conditions. In systems with a net charge this method has been found to exhibit unwanted artifactual behavior in both system pressure and energy. A number of correction terms have been developed to counter these artifacts are are currently being refined and tested. The PME method has been extended in several directions, allowing the study of finite systems and the evaluation of free energy differences. There has been a significant effort in improving the techniques used to model complex systems with a mixture quantum mechanics and classical mechanics. The major development involves the use of Gaussian delocalized MM charges and the double link atom. Improved techniques for examining the free energy of reaction paths is provided by developments of the REPLICA/PATH method in CHARMM (Chemistry at HARvard Macromolecular Mechanics). Although many of the parameter sets and models that are generally available are of the quality required for accurate simulation of macromolecular systems, there remains the need to weigh the relative merits of these sets for the specific types of systems studied. There are also numerous details such as the treatment of water and long-range electrostatics. Ongoing projects include: - Evaluation of CVFF, MMFF (Merck), and other nonstandard force fields - Development and use of a polarizable and flexible water model - Approximation of long-range interactions in macromolecular simulation using variants of the Ewald sum and the particle mesh Ewald methods - Evaluation and comparison of implicit and explicit water models for simulations examining the hydration of proteins - Evaluation of parameter sets